DNA Methylation Predicts Survival and Response to Therapy in Patients With Myelodysplastic Syndromes
| Autor: | Wei Zhu, Hagop Kantarjian, E. Lin, Lanlan Shen, Donald A. Berry, Yi Guo, Hussain I. Saba, Eli Estey, Jean Pierre J. Issa, Jaroslav Jelinek, Yasuhiro Oki, Saira Ahmed, Sherry Pierce, Yutaka Kondo, Jianqin Shan, Xuelin Huang |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Oncology Cancer Research medicine.medical_specialty Decitabine Polymerase Chain Reaction Disease-Free Survival Cohort Studies Young Adult Internal medicine Original Reports medicine Humans Multicenter Studies as Topic Aged Neoplasm Staging Randomized Controlled Trials as Topic Aged 80 and over business.industry Myelodysplastic syndromes Methylation DNA Methylation Middle Aged medicine.disease Survival Rate Treatment Outcome Clinical Trials Phase III as Topic CpG site Hypomethylating agent International Prognostic Scoring System Myelodysplastic Syndromes DNA methylation Immunology CpG Islands Female business Epigenetic therapy medicine.drug |
| Zdroj: | Journal of Clinical Oncology. 28:605-613 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2009.23.4781 |
| Popis: | Purpose The current classification systems of myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), do not fully reflect the molecular heterogeneity of the disease. Molecular characterization may predict clinical outcome and help stratify patients for targeted therapies. Epigenetic therapy using decitabine, a DNA hypomethylating agent, is clinically effective for the treatment of MDS. Therefore, we investigated the association between DNA methylation and clinical outcome in MDS. Patients and Methods We screened 24 patients with MDS for promoter CpG island methylation of 24 genes and identified aberrant hypermethylation at 10 genes. We then performed quantitative methylation analyses by bisulfite pyrosequencing of the identified genes in 317 patient samples from three independent studies and assessed relations between methylation and clinical outcome. Results In an initial training cohort of 89 patients with MDS, methylation frequencies of individual genes ranged from 7% to 70% and were highly concordant. Therefore, we defined a methylation z score based on all genes for each patient. We found that patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival (12.3 v 17.5 months, respectively; P = .04) and shorter median progression-free survival (6.4 v 14.9 months, respectively; P = .009). This methylation prognostic model was independent of age, sex, and IPSS group. Applied to two validation cohorts (228 patients), this model was confirmed as an independent prognostic predictor for survival. Although methylation at baseline did not correlate with clinical response to decitabine, we observed a significant correlation between reduced methylation over time and clinical responses. Conclusion DNA methylation predicts overall and progression-free survival in MDS. |
| Databáze: | OpenAIRE |
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